Description: (Applicant's Description) The Protease Program is primarily a basic science program with an expanding emphasis in translational research. The members of this program come from three institutions: Wayne State University and Henry Ford Health Systems in Detroit and the University of Windsor in Windsor, Ontario. The basic research of this program focuses primarily on determining the roles of proteases and their endogenous inhibitors in malignant progression. Proteases of the matrix metalloproteinase, cysteine (calpain, caspase and cathepsin), serine and aspartic classes are currently under study. In terms of protease inhibitors, program members are investigating both endogenous protease inhibitors (e.g., tissue inhibitors of matrix metalloproteinases and cystatins) and designing and testing novel synthetic inhibitors for matrix metalloproteinases and cysteine (calpain and cathepsin) proteases. Translational research efforts are directed toward: 1) determining whether the proteases and their endogenous inhibitors might serve as prognostic indicators, 2) development of protease inhibitors as potential therapeutic agents, 3) determining whether cell surface binding proteins for proteases and inhibitors might serve as prognostic indicators and novel targets for therapeutic intervention, and 4) developing novel methods for in vitro and in vivo imaging of proteases. This work includes interprogrammatic collaborations with investigators in the Prostate, Breast Cancer and Developmental Therapeutics programs. Other basic research of the Protease Program addresses more fundamental issues such as the mechanisms for intracellular trafficking and secretion of proteases, the molecular and cellular mechanisms for regulation of protease expression and activity, and the roles of proteases and their inhibitors in diseases other than cancer, in normal development and in apoptotic responses to cell injury. The latter studies represent an alternative approach to designing effective anti-tumor agents. As the basic and translational research efforts of the Protease Program are successful, we anticipate that novel agents will be generated for testing in preclinical and ultimately in clinical